Open AccessAGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer
Author(s) -
Jean C. Tien,
Seema Chugh,
Andrew Goodrum,
Yunhui Cheng,
Rahul Mannan,
Yuping Zhang,
Lisha Wang,
Vijaya L. Dommeti,
Xiaoming Wang,
Alice Xu,
Jennifer Hon,
Carson Kenum,
Fengyun Su,
Rui Wang,
Xuhong Cao,
Sunita Shankar,
Arul M. Chinnaiyan
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2026104118
Subject(s) - kras , cancer research , hras , neuroblastoma ras viral oncogene homolog , biology , cell growth , carcinogenesis , cancer , tumor progression , lung cancer , signal transduction , medicine , colorectal cancer , microbiology and biotechnology , genetics
Significance RAS proteins (HRAS, NRAS, and KRAS) integrate extracellular trophic signals to promote cell proliferation. Constitutively active KRAS drives tumor initiation and progression in nonsmall cell lung cancer (NSCLC). As RAS proteins are often refractory to direct pharmacological inhibition, RAS-interacting proteins are under investigation as potential drug targets. We previously found Argonaute 2 (AGO2) to bind RAS and positively regulate RAS-dependent signaling pathways.AGO2 knockdown blunted proliferation in NSCLC cells containing a KRAS-activating mutation. Here, we demonstrate that AGO2 promotes tumor progression in multiple mouse models of KRAS-driven NSCLC. In these animals,Ago2 knockout impairs tumor growth, lowers pathologic grade, and inhibits KRAS signaling. Targeting the AGO2-KRAS interaction may hold future therapeutic promise in NSCLC and other KRAS-driven malignancies.